Smart bandage

ABSTRACT

A sensing chip attached to a bandage monitors the healing process of a wound by detecting growth factors, thrombin and fibrinogen. The complementary metal-oxide semiconductor includes a functionalized working electrode, functionalized counter electrode and functionalized reference electrode. The healing progress is stimulated by generating oxygen in the wound.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/913,704, filed on Mar. 6, 2018, which, in turn, claimspriority to U.S. Provisional Application No. 62/471,493, filed on Mar.15, 2017, the disclosures of all of which are incorporated herein byreference in their entirety.

TECHNICAL FIELD

The present disclosure relates to monitoring wounds and acceleratingwound healing. More particularly, it relates to a smart bandage formonitoring of wounds.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings, which are incorporated into and constitute apart of this specification, illustrate one or more embodiments of thepresent disclosure and, together with the description of exampleembodiments, serve to explain the principles and implementations of thedisclosure.

FIG. 1 illustrates an exemplary smart bandage.

FIG. 2 illustrates an exemplary electrode setup for a sensor.

FIG. 3 illustrates an exemplary wafer with sensor chips.

FIG. 4 illustrates an exemplary smart bandage.

FIGS. 5-6 illustrate an exemplary reading device.

FIG. 7 illustrates an exemplary aptamer functionalization for theelectrodes.

SUMMARY

In a first aspect of the disclosure, a device is described, the devicecomprising: a bandage having a first surface configured to face a wound;a sensor attached to the bandage on the first surface.

In a second aspect of the disclosure, a method is described, the methodcomprising: providing a complementary metal-oxide semiconductor sensorchip comprising a working electrode, a counter electrode, and areference electrode, the working electrode, the counter electrode, andthe reference each having a gold surface; attaching the complementarymetal-oxide semiconductor sensor chip to a bandage; attaching a thiolgroup to a thrombin binding aptamer; and attaching the thrombin bindingaptamer with the thiol group to the gold surface of the workingelectrode, or of the counter electrode, or of the reference electrode.

DETAILED DESCRIPTION

The present disclosure describes a “smart bandage” for monitoring woundsand accelerating wound healing. Smart bandages can be fabricated byusing inexpensive complementary metal-oxide semiconductor (CMOS) chips,placed into conventional bandages. For example, the chips can be poweredwirelessly, or in any case capable of wireless communication. The chips,when attached to a bandage, are exposed to the complex chemistry of thewound. The chip can, for example, detect chemical or biologicalparameters in the wound. The sensor chips can, therefore, detect datawhich can indicate how a wound is healing or progressive. The data,communicated to a reader device, for example connected wirelessly to thechip, can then inform subsequent medical treatments. The medicaltreatments can therefore be more effective as they are based on detailedinformation of the state of the wound.

The possibility to create inexpensive, disposable smart bandages relieson the ability to produce and functionalize millimeter-scale CMOS chips,for example with a cost of approximately 10 cents/chip, usingvolume-based fabrication methods. This in turn can make smart bandagesviable for a large market.

The process of wound healing can be summarized by the following sequenceof events. When the skin is cut or scraped, bleeding starts. Blood cellsbegin to clump together and clot, instructed by proteins such asthrombin and fibrinogen. These protect the wound and prevent furtherblood loss (hemo stasis). The clots, which turn into scabs and dry, arecreated by platelets, and contain fibrin, which forms a net to hold theclots in place.

Once the wound is closed with a clot, the blood vessels can open a bitto allow fresh nutrients and oxygen into the wound for healing. Oxygenis essential for healing, and the right balance of oxygen is veryimportant. Too much or too little oxygen will prevent the wound fromhealing correctly. Macrophages (white blood cells) are used to fightinfection and clear fluid is often expelled around the cut at that time.Macrophages also release growth factors that help repair the wound. Thisprocess is followed by strengthening of the repaired tissue, which is aprocess that can take several months.

The two important initial wound healing processes of hemostasis andinflammation are normally taken for granted and are not monitored verycarefully. These typically take several days. Unfortunately, a woundthat is not receiving enough blood could take at least twice as long toheal, if it heals at all. It is estimated that 6.5 million people in theUnited States suffer with wounds that are not healing well. Difficultiesin wound healing often occur in populations that suffer from chronicwounds, typical in populations with diabetes, high blood pressure,obesity and other vascular disease.

The present disclosure describes the concept of inexpensive CMOS chipsintegrated in bandages or similar items. For example, FIG. 1 illustratesa band-aid or adhesive bandage, a common household item, which comprisesan adhesive part (105), a gauze part (110), and a sensor chip (115). Thesensor chip could also be integrated in gauze which is not part of anadhesive bandage or band-aid, but part of a strip of cloth or similarmaterial that can be applied to a wound, for example by wrapping itaround an arm or torso.

The chip attached to the bandage can monitor the process of hemostasisand inflammation, as well as identify infections in wounds. In someembodiments, the chips can also be modified to generate and measureoxygen locally in their surroundings, and carry chemistries that can bereleased on command. A reader device can be used to power andcommunicate with these chips, for example through a near-field inductivecoil “antenna”.

Currently, wound healing is generally monitored by visual observation.The personal experience of the health practitioner monitoring the woundis used to determine the progression of the healing process.Occasionally, molecular diagnostic tools need to be used to evaluate thechemistry of this process. Given the low anticipated cost of thediagnostic systems described in the present disclosure, as well as thelarge opportunities for adapting diagnostic chips for different types ofinjuries, wound healing chips will be very competitive as a valueaddition to the bandage market, which has experienced a lack ofinnovation over the past decades.

One of the key advantages of using CMOS electronic chips as the basisfor medical diagnostic measurements is the ability to leverage technicalknowledge in the consumer electronics industry, into the fabrication ofsmall but complex medical devices. In some embodiments, the smartbandage can comprise a wireless platform. The smart bandage can comprisea potentiostat chip to measure glucose in diabetes patients, containing,for example, 10,000 transistors and a wireless RF tag circuit linkoperating at 800-900 MHz to power and communicate with the readerdevice. For medical applications, the contact surfaces, typicallyaluminum-silicon alloys, can be to coated with platinum. Additionally,enzymes can be applied to these contact surfaces to functionalize thechips for the measurement of specific analytes (such as lactate,pyruvate, glucose, etc). This post-processing adds a fixed cost perdevice, but can be automated and performed at the wafer scale. FIG. 3illustrates how multiple chips (310) can be fabricated on a single wafer(305) to decrease costs.

To read the sensor chips, a standard radiofrequency (RF) tag reader canbe used. These tag readers have been developed for identification andtracking of materials and are commercially available. For example, an RFtag reader can be used for continuous glucose monitoring by connectingto the chip in the bandage and communicate with the chip continuously.

In some embodiments, it is possible to measure glucose by using theconversion of glucose into gluconic acid and hydrogen peroxide with theassistance of an enzyme—glucose oxidase or glucose dehydrogenase. Forexample, a standard set up comprising a working electrode, a counterelectrode, and a reference electrode can be used. The current on theworking electrode measures the hydrogen peroxide ion current resultingfrom the glucose reaction, and this current is proportional to theglucose concentration if the chemistry is well-controlled (i.e., enoughoxygen is supplied to enable this reaction).

FIG. 2 illustrates an exemplary set of electrodes which can befabricated on a surface of the chip, to face towards the wound whenapplying the smart bandage. For example, a working electrode (215), acounter electrode (205) and a reference electrode (210) can befabricated as concentric squares, or other similar shapes. Theseelectrodes can be functionalized to detect different biological entitiesin a wound, such as thrombin, fibrinogen, and growth factors, or others.For example, biological agents can be attached to the metallic surfaceas functionalization.

In other embodiments, the chips of the present disclosure can use thesame powering and communications platform as the glucose monitoringchips, but can be able to measure thrombin, fibrinogen, and growthfactors by using aptamer binding chemistry combined with conductivitymeasurements. Electrochemical oxygenation measurements can also bepossible, along with the deliberate generation of oxygen throughelectrochemical dissociation of water. Physiological data, such as localchip temperature, can also be included into the sensor to enable theobservation of the inflammation process. The combination of thesemeasurements is able to provide an indication of the healing process, aswell as an opportunity for early detection of infection.

FIG. 4 illustrates an exemplary adhesive bandage comprising an adhesivepart (405), a gauze part (415), and a chip (410).

As known to the person of ordinary skill in the art, thrombin is aserine protease, an enzyme that cleaves peptide bonds in a protein.Fibrinogen is a glycoprotein that circulates in the blood. In a tissueor vascular injury, fibrinogen is converted enzymatically by thrombin tofibrin and subsequently to a fibrin-based blood clot. Fibrinogenfunctions primarily to occlude blood vessels and thereby stop excessivebleeding. Aptamers are oligonucleotide or peptide molecules that bind toa specific target molecule. Aptamers can be created by selecting themfrom a large random sequence pool. Nucleic acid aptamers are nucleicacid species that have been engineered through repeated rounds ofselection or evolution to bind to molecular targets such as smallmolecules, proteins, nucleic acids, cells, or tissues. Peptide aptamersare artificial proteins selected or engineered to bind specific targetmolecules. Therefore, aptamers can be used to bind selectively to adesired biomolecular target, for example thrombin or fibrinogen. In thisway, aptamers can be used to detect the presence and quantity ofthrombin or fibrinogen. In some embodiments, the thrombin bindingaptamer is attached to the surface of the electrodes in the sensing chipin the smart bandage. Upon binding to thrombin, the aptamer can becomedissociated from the electrode surface, thus originating an electricalsignal at the chip. For example, the impedance would change due to thesurface change at the electrodes subsequent to target binding.Voltammetry measurements with a working electrode, counter electrode andreference electrode could be used. Generally, amperometric,voltammetric, or impedimetric signals for detection of thrombin or otherbiomolecular markers of wound healing can be used by the chip to monitorthe evolution of the state of the wound.

For example, the thrombin binding aptamer can be attached to a goldelectrode surface. The displacement event of the binding aptamer isbased on the propensity of single-stranded DNA to readily absorb onto agold surface, and to subsequently desorb upon binding to the aptamer'starget, for example thrombin. A thiol functional group can be added tothe binding aptamer for covalent binding to the gold surface. Otheraptamers can be used to detect other biomolecular targets instead ofthrombin.

For example, aptamers for human thrombin detection can be based on twonon-overlapping DNA thrombin aptamers. As another example, thrombinbinding to an immobilized thrombin binding aptamer on the surface of thechip can enable the chip to detect thrombin. For example, the aptamerscan be attached to the surface of the electrodes to detect thrombin.Upon attachment, the electrical characteristic of the electrode wouldchange, enabling the chip to detect the change in current or voltage.

The functionalized chips can be tested in-vitro to ensure that theaptamer chemistry is stable, contacts can be kept clean and active, andthe sensors can provide quantitative information on the hemostatis andinflammation chemistries for several days. As the smart bandages do notinvolve a permanent implant, but will be disposed with the bandage afterthe wound is healed, it is expected that a lengthy FDA approval processcan be avoided. Initial toxicology tests on the CMOS chips have revealedno change in the surrounding chemistry even after 3 months of exposureto tissue.

Currently, wound healing is performed using very empirical approaches.After cleaning of the wound and the application of a bandage, the woundis occasionally monitored, and infection is avoided. The collection ofquantitative data with the smart bandages of the present disclosureallows development of an analytical molecular diagnostic tool to measurethe healing progression and provide immediate feedback information toboth patient and practitioner.

Wound care is predicted to grow modestly over the forecast period, withvalue sales increasing by 8% in constant 2013 terms to reach US $892million in 2018. Gashes and cuts are a part of everyday life, and whileenough people maintain an active lifestyle, they will continue to buybandages at about the same rate as they have before.

The present disclosure describes a device which employs a CMOS microchipchemical sensor embedded in a bandage. The sensor chip can be eitherbattery powered or remotely powered through inductive coupling of RFfrequency power (RF tag), or through an infrared laser or LED. A CMOSchip can measure either conductivity changes on a working electrode ofan electrochemical cell or ion current from an enzyme reaction ordielectric constant changes. The measurement circuit is a CMOS siliconcircuit that can be manufactured in a standard CMOS fabrication line

The present disclosure describes a bandage that can be used as areservoir to supply an enzyme or other chemistry for a chemical reactionthat can accelerate wound healing. A CMOS chip circuit can provideenough voltage to electrochemically generate oxygen or chlorine(depending on the applied electrochemical potential) to change thechemistry in a wound. A CMOS chip can report the measured current,conductivity or dielectric constant out to a reader. For example, FIG. 5illustrates a reader device (505) comprising an area which cancommunicate wirelessly (510) to the sensing chip in a smart bandage.FIG. 6 illustrates the reader (605) and the chip reading area (610). Anexemplary reader uses a coil to power and receive information from thesensor chip. For example, the reader can have a range of 5 mm, ideal formonitoring wounds with smart bandages.

In some embodiments, multiple CMOS chips in a smart bandage can measuredifferent chemistry in the same bandage. A CMOS chip can measure severalmolecule concentrations simultaneously by using multiple binding orenzyme chemistries on the same electrochemical electrode or on separateelectrochemical electrodes. A CMOS chip in a bandage can determinewhether the wound has healed or not. A CMOS chip in a bandage candetermine whether the wound is infected (sepsis) by measuring localtemperature or chemistries indicating infection. A CMOS chip in abandage can determine whether there is enough oxygen to facilitate woundhealing, and can regulate the oxygen electrochemically. In someembodiments, the CMOS chip comprises a coil to receive power from thewireless reader, and to communicate with the reader.

FIG. 7 illustrates an exemplary functionalization of electrode surfacesfor the chips in a smart bandage. For example, the chip as illustratedin FIG. 1 may have a working electrode, counter electrode and referenceelectrode in a configuration such as that of FIG. 2, or other, differentconfigurations. The electrodes may, in some embodiments, be made ofgold, or have a gold layer as the top surface to be in contact with thewound when the bandage is applied. The electrodes may have afunctionalization agent attached to the top surface. For example, if thesurface is made of gold, or if the electrode is made of gold, the thiolchemistry may be used to attach biomolecular entities to the electrodesurface. One or more of the electrodes may be functionalized in thisway. For example, a thrombin binding aptamer with thiols may be attachedto the electrode surface. In this way, the electrode can react to thepresence and quantity of thrombin and monitor healing of the wound basedon the amount of thrombin. For example, the chip can monitor the amountof thrombin as a function of time.

In FIG. 7, the electrode surface (705) is functionalized with afunctionalizing agent (710) such as a thrombin binding aptamer. Otheraptamers or other functionalizing agents may also be used to detectother molecular targets other than thrombin. In some embodiments, theelectrodes may also comprise more than one functionalizing agent inorder to detect more than one molecular target.

A number of embodiments of the disclosure have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the presentdisclosure. Accordingly, other embodiments are within the scope of thefollowing claims.

The examples set forth above are provided to those of ordinary skill inthe art as a complete disclosure and description of how to make and usethe embodiments of the disclosure, and are not intended to limit thescope of what the inventor/inventors regard as their disclosure.

Modifications of the above-described modes for carrying out the methodsand systems herein disclosed that are obvious to persons of skill in theart are intended to be within the scope of the following claims. Allpatents and publications mentioned in the specification are indicativeof the levels of skill of those skilled in the art to which thedisclosure pertains. All references cited in this disclosure areincorporated by reference to the same extent as if each reference hadbeen incorporated by reference in its entirety individually.

It is to be understood that the disclosure is not limited to particularmethods or systems, which can, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting. As used in this specification and the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontent clearly dictates otherwise. The term “plurality” includes two ormore referents unless the content clearly dictates otherwise. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which the disclosure pertains.

The references in the present application, shown in the reference listbelow, are incorporated herein by reference in their entirety.

1.-2. (canceled)
 3. A disposable wound-healing monitoring devicecomprising: a bandage having a first surface configured to face a wound;a sensor attached to the bandage on the first surface, the sensorcomprising a complementary metal-oxide semiconductor chip, thecomplementary metal-oxide semiconductor chip comprising an electrode;and a selectively thrombin-binding or selectively fibrinogen-bindingaptamer attached to a wound-facing surface of the electrode, wherein thecomplementary metal-oxide semiconductor chip is configured to monitor anamount of thrombin or fibrinogen in the wound as a function of time bydetecting over time an absence or presence of thrombin or fibrinogen inthe wound based on the selectively thrombin-binding aptamer binding ornot binding to thrombin or the selectively fibrinogen-binding aptamerbinding or not binding to fibrinogen, and generating a correspondingsignal, thereby monitoring healing of the wound over time.
 4. The deviceof claim 3, wherein the sensor is configured to generate oxygen withinthe wound.
 5. The device of claim 4, wherein the sensor is configured tobe powered wirelessly by a reader device, and to communicate wirelesslywith the reader device.
 6. The device of claim 5, wherein the sensor andthe reader device each comprise a coil, the coils configured to transmitpower to the sensor and to communicate between the sensor and the readerdevice.
 7. The device of claim 3, further comprising a thiol groupattached to the thrombin binding aptamer.
 8. The device of claim 3,wherein the electrode is made in a form of concentric shapes.
 9. Thedevice of claim 8, wherein the concentric shapes comprise squares. 10.The device of claim 8, wherein the electrode is fabricated on a surfaceof the complementary metal-oxide semiconductor chip.
 11. The device ofclaim 3, further comprising glucose oxidase or glucose dehydrogenase onthe electrode, the device being configured to measure a current on theelectrode, thereby measuring glucose.
 12. The device of claim 3, whereinthe complementary metal-oxide semiconductor chip is configured tomeasure a process of hemostasis and inflammation to identify infectionsin wounds.
 13. A method comprising: providing a complementarymetal-oxide semiconductor sensor chip comprising an electrode having aconductive surface; attaching the complementary metal-oxidesemiconductor sensor chip to a bandage; attaching a selectivelythrombin-binding or selectively fibrinogen-binding aptamer to theconductive surface of the electrode, the conductive surface configuredto face a wound; monitoring an amount of thrombin or fibrinogen in thewound as a function of time by detecting over time an absence orpresence of thrombin or fibrinogen in the wound based on the selectivelythrombin-binding aptamer binding or not binding to thrombin or theselectively fibrinogen-binding aptamer binding or not binding tofibrinogen, and generating a corresponding signal, thereby monitoringhealing of the wound over time.